DNAH1 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by structural and functional defects in motile cilia leading to chronic respiratory infections, bronchiectasis, and infertility. The axonemal dynein heavy chain 1, encoded by DNAH1, is a critical motor protein responsible for ciliary and flagellar beating. Loss of DNAH1 function disrupts outer dynein arms and impairs mucociliary clearance, predisposing to recurrent respiratory infections and male infertility. Genetic variation in DNAH1 has emerging evidence for PCD etiology, particularly in cohorts with negative findings in common PCD genes.

Initial evidence came from a consanguineous Saudi Arabian family with two affected sisters harboring a homozygous missense variant c.3460A>C (p.Lys1154Gln) that segregated fully with Primary Ciliary Dyskinesia phenotype (PMID:25927852). Subsequent neonatal and multicenter studies identified DNAH1 variants in children diagnosed with PCD in high consanguinity populations, although specific allele counts per cohort were limited (PMID:38679661). Genotype screenings in Chinese, Turkish, and European cohorts further uncovered compound heterozygous missense and truncating variants, including p.Arg148Cys and p.Trp870Ter, in singleton and small series of PCD patients (PMID:31507630, PMID:31765523, PMID:35869935, PMID:33577779).

Across these studies, at least ten unrelated probands from six families exhibited biallelic DNAH1 variants. The variant spectrum includes multiple missense substitutions such as c.3460A>C (p.Lys1154Gln) and c.442C>T (p.Arg148Cys), as well as premature termination alleles like c.2610G>A (p.Trp870Ter). No recurrent founder variants have been consistently reported, and carrier frequency data are unavailable. All reported cases follow an autosomal recessive inheritance pattern with complete segregation in affected sibships.

Functional assessment using a ferf1 mouse model demonstrated that a Dnah1 missense mutation p.Thr2231Met resulted in abnormal sperm motility and fertilization failure, mirroring human dynein dysfunction and supporting a loss-of-function mechanism (PMID:30734403).

However, transmission electron microscopy studies in adults with inconclusive genotypes revealed individuals carrying VUS in DNAH1 with normal ciliary ultrastructure, underscoring potential variant-specific effects or incomplete penetrance (PMID:37998386).

In summary, cumulative genetic and experimental data support a moderate association between DNAH1 and primary ciliary dyskinesia. Further large-scale segregation analyses and functional characterization of variants are needed. Key take-home: DNAH1 should be considered in diagnostic gene panels for PCD, particularly in consanguineous populations with unresolved cases.

References

• BMC medical genetics • 2015 • Variation in DNAH1 may contribute to primary ciliary dyskinesia. PMID:25927852
• European journal of pediatrics • 2024 • Neonatal diagnosis of primary ciliary dyskinesia in a high consanguinity population: a single tertiary center experience. PMID:38679661
• Frontiers in genetics • 2019 • Identification of Pathogenic Mutations and Investigation of the NOTCH Pathway Activation in Kartagener Syndrome. PMID:31507630
• Pediatric pulmonology • 2020 • Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: First results from Turkey. PMID:31765523
• American journal of medical genetics. Part A • 2022 • Pathogenic variants identified using whole-exome sequencing in Chinese patients with primary ciliary dyskinesia. PMID:35869935
• Chest • 2021 • Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China. PMID:33577779
• Cells • 2023 • Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype. PMID:37998386
• Molecular reproduction and development • 2019 • ENU-induced mutant allele of Dnah1, ferf1, causes abnormal sperm behavior and fertilization failure in mice. PMID:30734403

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